Calcitonin is a 32 amino acid polypeptide hormone secreted by the parafollicular or C cells of the thyroid gland in response to elevated blood levels of calcium. This hormone decreases blood calcium (hypocalcemic activity) primarily by inhibiting bone resorption through plasma membrane-associated receptors on the osteoclast. High-turnover bone loss, as seen with hypercalcemia of malignancy, estrogen withdrawal as following the onset of the menopause, and certain anti-inflammatory or arthritis therapies, has recently been shown to be preventable by the administration of calcitonin (Bilezikian, J. P., J. Fert. Menopausal Studies. 1996, 41, 148-155). As recently demonstrated for post-menopausal osteoporosis, treatment leads to not only a maintenance of bone mass and total body calcium, but also to decreases in the incidence of hip and vertebral fractures [Rico, H., et al., Calcif. Tissue Int. 1995, 56, 181-185, Gennari, C., Aust. Family Physician. 1994, 48, 196-200. Thus, it is apparent that calcitonin is an appropriate therapeutic for the prevention and treatment of osteoporosis by virtue of its hypocalcemic activity.
Although calcitonin has demonstrated efficacy in the prevention of high-turnover bone loss, a limitation for its wide-spread use is the lack of oral bioavailability, necessitating administration by parental (intra-muscular) or nasal routes. However, stimulation of endogenous calcitonin synthesis and release by inducer compounds would be expected to result in a similar therapeutic effect. This invention describes the ability of a series of xanthine sulfonamides to induce the expression and release of endogenous calcitonin, an activity not previously described for these compound.
Smith et al. disclose a class of 6-aminoxanthine-7-sulfonamides, 6-amino-sulfonylxanthine-7-sulfonamides and 6-aminobis(sulfonyl)xanthine-7-sulfonamides as phosphodiesterase (PDE) inhibitors in U.S. Pat. No. 5,409,934 and J. Med. Chem. 1994, 37, 476-85. Ginger et al. disclose of series a xanthine-7-sulfonamides as bronchodilating agents in U.S. Pat. No. 3,900,474.
The synthesis of variously substituted xanthine sulfonamides are described in the following publications: Buckle et al., J. Med. Chem. 1994, 37, 476-85, Primenko et al., Ukr. Khim. Zh. (Russ. Ed.) 1985, 51, 660-3, Acatrinei et al, An. Stint. Univ. "Al. I Cuza" lasi, Sect. 2a, 1974, 20, 247-52.